ArticleCureus2026
Third-Space Entrapment of Methotrexate in Anthracycline-Induced Cardiomyopathy: The First Complete Case Trajectory From Toxicity to Rescue Failure.
Article in Cureus, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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4 authors.
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Abstract
Methotrexate (MTX) is vital for treating multiple malignancies, including central nervous system (CNS) hematologic malignancies, but toxicity is a major limitation. Anthracyclines, cornerstones of lymphoma therapy, can cause cardiomyopathy, which may alter drug kinetics. This case highlights catastrophic MTX toxicity precipitated by prior anthracycline-induced cardiomyopathy. A 64-year-old with diffuse large B-cell lymphoma (DLBCL) and anthracycline-induced cardiotoxicity was admitted for CNS-directed MTX therapy. Despite standard prophylaxis and prior tolerance, the patient developed anuria, hypotension, and cardiogenic shock following infusion. Serum MTX peaked at >600 μmol/L. Bedside imaging revealed a reduced ejection fraction and a large pleural effusion. Despite receiving glucarpidase and high-flux dialysis, MTX levels remained persistently elevated. Thoracentesis confirmed third-space sequestration with pleural MTX levels of 89 μmol/L. Clearance required 35 days of continuous dialysis and leucovorin rescue before levels fell below 0.1 μmol/L. The patient suffered cardiogenic shock and encephalopathy before transitioning to comfort care. This case illustrates how anthracycline-induced cardiomyopathy potentiates MTX toxicity through three mechanisms: decreased systemic circulation, cardiorenal syndrome-mediated reduced excretion, and increased third-space sequestration due to venous stasis. These factors trigger a deleterious cycle of multi-organ failure. This trajectory underscores the role of cardiomyopathy-induced effusions as reservoirs for third-space entrapment, which creates a pharmacological barrier leading to definitive rescue failure despite aggressive systemic detoxification and high-flux hemodialysis. Clinicians must recognize cardiomyopathy as a critical risk factor for MTX sequestration and toxicity, regardless of whether prior cycles were tolerated. Early recognition of third-spacing and multidisciplinary management are essential to improve outcomes in high-risk cardio-oncology patients.
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